Growth Factor Pathways in Development of Endocrine Resistance in Human Breast Cancer Cells

Ray, Swagat (2010) Growth Factor Pathways in Development of Endocrine Resistance in Human Breast Cancer Cells. PhD thesis, University of Reading.

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Item Type:Thesis (PhD)
Item Status:Live Archive

Abstract

Growth of MCF7 McGrath human breast cancer cells (MCF7) under conditions of longterm oestrogen deprivation results in loss of oestrogen dependence for growth (MCF7‐ED) and provides a model system to study the molecular basis of endocrine resistance in breast cancer. MCF7‐ED cells had higher levels of phosphorylated mitogen activated protein kinase (MAPK) than MCF7 cells. However, since a similar increase in
phosphorylated MAPK was found in MCF7 cells within hours of insulin withdrawal from the medium, and as the growth rate of the MCF7‐ED cells in the absence of oestrogen was only marginally affected by the MAPK inhibitors PD98059 (2.5‐20μg/ml) and U0126 (2.5‐10μM), it would seem that raised levels of phosphorylated MAPK are a response to insulin withdrawal rather than a mechanism for enhanced basal growth.
By contrast, although no difference in levels of phosphorylated‐Akt (Thr308/Ser473) were observed between MCF7 and MCF7‐ED cells, the growth rate of the MCF7‐ED cells in the absence of oestrogen was inhibited by the inhibitor of phosphatidylinositol 3‐kinase (PI3K), LY294002 (2.5‐10μM). The IGF1R inhibitor Picropodophyllin (PPP) also inhibited growth of the MCF7‐ED cells and decreased phosphorylation of Akt and p‐
70S6K, a major downstream target of mTORC1. The mTORC1 inhibitor rapamycin could decrease the growth of stock MCF7‐ED cells but not MCF7 cells suggesting a mechanistic role of PI3K/Akt/mTORC1 in oestrogen independence. Combination of rapamycin (1nM) with LY294002 (2.5‐10μM) revealed greater growth inhibition of MCF7‐ED cells than when added alone which may be explained by blocking the
negative feedback loop that exists between mTORC1/p‐70S6K and PI3K. Comparison with other cell models showed that long‐term oestrogen deprived T47D cells exhibited even greater sensitivity towards rapamycin alone or in combination with LY294002. In ZR‐75‐1 cells, however, rapamycin alone or in combination with LY294002 could inhibit growth of the oestrogen maintained as well as the oestrogen deprived cells. The above findings thus reinstate the emerging potential of combination therapy with mTOR and PI3K inhibitors in breast cancer.

Keywords:Breast cancer
Subjects:C Biological Sciences > C130 Cell Biology
Divisions:College of Science > School of Life Sciences
ID Code:37151
Deposited On:02 Oct 2019 09:00

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